Compounds and methods for treating aberrant adrenocartical cell disorders

Abstract

Methods and compositions are provided for treatment of disorders associated with aberrant adrenal cortex cell behavior, including (but not limited to) treatment of adrenocortical carcinoma (ACC), Cushing's syndrome and / or pituitary ACTH excess (Cushing's Disease). Such methods involve administration of an effective amount N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea hydrochloride to the patient.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 61 / 614,269 filed on Mar. 22, 2012, which application is incorporated by reference herein in its entirety.GOVERNMENT SUPPORT[0002]This invention was made with government support under DA030339 and GM086213 awarded by the National Institutes of Health. The government has certain rights in this invention.BACKGROUND[0003]1. Technical Field[0004]Methods and compositions are provided for treatment of disorders associated with aberrant adrenal cortex cell behavior.[0005]2. Description of the Related Art[0006]The adrenal gland is made up of two parts: the outer cortex in which certain hormones are produced, and the inner medulla which is part of the nervous system, wherein nervous system hormones are produced. The cortex is devoted to the synthesis of corticosteroid and androgen hormones. Specific cortical cells produce particular hormones including ald...

AI Technical Summary

Benefits of technology

This patent describes methods for treating various disorders or conditions by administering a therapeutically effective amount of N-(2,6-bis(l-methylethyl)phenyl)-N′-((l(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea hydrochloride (ATR-101) to a patient. These methods include treating adrenocortical carcanoma, benign adenoma, increased hormone production, metastatic adrenocortical carcanoma, congenital adrenal hyperplasia, Cushing's syndrome, excess cortisol production, symptoms associated with excess cortisol production, hyperaldosteronism, or 21-hydroxylase deficiency. The methods may also involve using a second therapeutic agent such as chemotherapy, mitotane, mifepristone, metformin, everolimus, a targeting agent, an adrenolysis agent, or an IGFR antagonist. The patent also discusses oral administration of ATR-101 and the option of daily or multiple doses. The composition may include ATR-101 and a second therapeutic agent in a unit dose, such as mifepristone, a chemotherapy agent, metformin, everolimus, a targeting agent, an adrenolysis agent, or an IGFR antagonist. Overall, the patent provides a method for treating various disorders or conditions by targeting the aberrant production of adrenal hormones.

Problems solved by technology

Likewise, adrenocortical carcinomas can lead to hormone production that can cause noticeable body changes such as weight gain, fluid build-up, early puberty in children, or excess facial or body hair in women.

While the understanding of the disease has advanced with the advent of modern molecular techniques, the prognosis of patients with advanced disease, who represent about half of the diagnoses, remains dismal.

The drug requires chemical transformation into an active, free radical form, which then induces lipid peroxidation and cell death.

Mitotane has numerous problems as a therapeutic agent, making its use difficult, and requiring close monitoring of patients.

These problems include:Severe side effects: practically all patients experience gastrointestinal dysfunctions and CNS symptoms.

Even with a high drug intake by patients, it takes several months to reach target therapeutic blood levels.

Mitotane interferes with the metabolism of other drugs, making medical management of the many debilitating symptoms and additional chemotherapy of ACC patients challenging (Kroiss, M., et al., Clin.

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